Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibody-based treatment is a novel, effective management strategy for a variety of diseases. Alemtuzumab (CAMPATH) is an example of a monoclonal antibody (mAb) that was initially developed in the laboratory and has completed its journey by being approved for therapeutic use in humans. The main clinical applications of alemtuzumab include treatment of lymphoid malignancies, particularly chronic lymphocytic leukaemia (CLL) and T-cell prolymphocytic leukaemia (T-PLL) and prevention of graft versus host disease (GVHD) and graft rejection in bone marrow and solid organ transplant recipients. Alemtuzumab administration is accompanied by a characteristic first-dose reaction due to cytokine release that consists of fever, rigors, rash and, at times, dyspnea and hypotension. The most significant toxic effect is profound, prolonged lymphopenia and the subsequent increased risk of opportunistic infections; antibiotic prophylaxis is recommended for patients undergoing alemtuzumab treatment. Alemtuzumab has demonstrated clinical activity as a single agent and has an acceptable toxicity profile. It has significant therapeutic potential, especially against lymphoid malignancies.
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PMID:Alemtuzumab: a novel monoclonal antibody. 1172 36

Graft-versus-host disease (GVHD), a major complication after allogeneic transplantation, can be abrogated by the Campath (anti-CD52) monoclonal antibody. The induction of acute GVHD requires host antigens to be presented to donor T cells by antigen-presenting cells (APCs). Recent evidence has suggested that only host APCs can interact with donor T cells in the induction of GVHD. Because CD52 has been reported to be expressed on DCs, we reasoned that pretransplant Campath-1G might have a direct effect on circulating DCs in addition to any effects on donor T cells. Using direct immunostaining, we demonstrated expression of CD52 on DCs and that Campath-1G killed purified DCs in vitro. In vivo Campath also depleted DCs. Twenty-four hours after the first dose of Campath-1G, circulating DCs were reduced by a mean of 79% (range, 44%-96%). By day 0 after 5 doses of Campath-1G and chemoradiotherapy conditioning, DCs became undetectable in 7 of 9 cases, whereas in 6 of 7 patients receiving conditioning therapy without Campath-1G, host DCs were still detectable. The reconstitution of circulating DCs after transplantation was not affected by Campath-1G and in both groups DC1 (CD11c(+)) recovered more rapidly than DC2 (CD11c(-)). Analysis of chimerism confirmed that the DCs recovering after transplantation in patients receiving Campath-1G were of donor origin. We conclude that in vivo Campath-1G causes a rapid depletion of host circulating DCs and that this may, in part, explain the low incidence of acute GVHD. The reconstitution of donor DCs was not delayed, which may be important in preserving immune reconstitution.
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PMID:Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution. 1189 97

Alemtuzumab, otherwise called CAMPATH-1H, is a humanized monoclonal antibody directed against the CD52 antigen of lymphocytes. It is one of a family of CAMPATH-1 antibodies that have been used over the last 20 yr in stem cell transplantation for depletion of donor and recipient T-cells to prevent graft-versus-host disease and graft rejection. Clinical trials have been carried out by a cooperative group of physicians and the protocols have gradually evolved as different problems have been identified and overcome. T-cell depletion carries risks of reducing graft-versus-tumor effects and increasing susceptibility to virus reactivation, but offers significant benefits in terms of reduced mortality and morbidity from graft-versus-host disease (GVHD). Two protocols are currently favored: (1) simple addition of CAMPATH-1H to the stem cell infusion and (2) administration in vivo prior to the transplant--especially in the context of nonmyeloablative conditioning regimens. Both of these give excellent control of GVHD with minimal graft rejection. Contrary to earlier expectations, a short course of posttransplant cyclosporin A (CyA) appears to further reduce transplant-related mortality, mainly by a reduction in late deaths from infection. These results need to be consolidated by means of prospective clinical trials.
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PMID:Alemtuzumab in stem cell transplantation. 1218 Apr 91

We report the outcome of nine unrelated bone marrow transplants performed for acquired severe aplastic anaemia at a single centre. Six patients received transplants from fully matched donors. Three donor/recipient pairs were mismatched, two at a single allele on high resolution typing. Pre-transplant conditioning consisted of cyclophosphamide and in vivo Campath-1 monoclonal antibody. One patient also received total body irradiation (TBI), and another patient with a coexisting paroxysmal nocturnal haemoglobinuria (PNH) clone received additional busulphan. Cyclosporin A was given for 12 months as prophylaxis against graft-versus-host disease (GVHD). Six of nine patients are alive and transfusion independent with a mean follow-up of 24 months (range: 1.5-94). All six patients who received fully matched transplants are alive; the three who received mismatched grafts died. Four long-term survivors developed autologous haematological recovery following rejection of their grafts. Acute GVHD grade II+ occurred in two patients. We highlight the importance of high-resolution HLA typing, including Cw matching in reducing the incidence of graft rejection and GVHD, resulting in improved survival in our patient group. This study also shows that autologous recovery with long-term survival can occur following non-irradiation conditioning regimens.
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PMID:Autologous recovery following non-myeloablative unrelated donor bone marrow transplantation for severe aplastic anaemia. 1218 7

Conventional allogeneic stem cell transplantation (SCT) for myelodysplastic syndrome (MDS) is associated with excessive procedure-related mortality. The outcome following volunteer-unrelated donor (VUD) or sibling allogeneic SCT was therefore evaluated in 23 MDS patients conditioned with reduced-intensity regimens (fludarabine/busulphan/Campath-1H) because of advanced age (48 vs 37 years, P = 0.002) and/or co-morbidity (19 vs 3, P < 0.0001) which precluded conventional transplantation, and compared with 29 treated with standard protocols [busulphan/cyclophosphamide (Bu/Cy); Bu/Cy/total-body irradiation/Campath-1G]. Graft-versus-host disease (GVHD) prophylaxis comprised of cyclosporine/methotrexate. One hundred per cent donor engraftment (variable number tandem repeat analysis/cytogenetics/fluorescence in situ hybridization) was achieved in 18/19 (95%) evaluable patients receiving reduced-intensity regimens, although six (32%) have subsequently shown mixed chimaerism. Reduced-intensity conditioning was associated with significantly reduced duration of aplasia, less mucositis, fever, antibiotic, analgesia, parenteral nutrition use, less acute and chronic GVHD, and lower early procedure-related mortality [two (9%) vs nine (31%), P < 0.05]. Six patients relapsed (two standard, four reduced-intensity) and two (reduced-intensity) experienced late graft failure. The 2 year actuarial overall/disease-free survival (OS/DFS) was 48/39% in the reduced-intensity arm and 44/44% in the standard group. The 2 year non-relapse mortality was 31% and 50% respectively. In VUD recipients, OS was superior in the reduced-intensity arm (49%vs 34%). Predictors of DFS included good/intermediate-risk karyotype, low/intermediate-1 International Prognostic Scoring system score, human leucocyte antigen compatibility and attainment of complete remission. Our data demonstrates that VUD or sibling allogeneic SCT following reduced-intensity conditioning is feasible in high-risk MDS patients considered unsuitable for standard transplantation and is associated with comparable 3.5 year DFS to those receiving conventional regimens.
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PMID:Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. 1235 19

Alemtuzumab (anti-CD52; Campath 1-H) depletes both host and donor T cells when used in preparative regimens for allogeneic transplantation. This promotes engraftment even after nonmyeloablative conditioning and limits graft-versus-host disease (GVHD) even after unrelated or major histocompatibility complex (MHC) disparate allografts. We asked whether anti-CD52 differentially targets antigen-presenting cells (APCs), in addition to depleting T cells. Monocyte-derived dendritic cells (moDCs) expressed abundant CD52 as expected. Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs), however, never expressed CD52. Immunostaining of skin and gut confirmed the absence of CD52 on these resident DC populations under both steady-state and inflammatory conditions. Although anti-CD52 functions primarily by antibody-dependent cellular cytotoxicity (ADCC) in vivo, assessment of its activity in vitro included complement-dependent lysis of CD52(+) cells. Anti-CD52 did not impair DC-T-cell adhesion, diminish DC-stimulated T-cell proliferation, or alter moDC development in vitro. We propose that anti-CD52 abrogates GVHD not only by T-cell depletion, but also by removing moDCs and their precursors. This would mitigate moDC phagocytosis and presentation of host-derived antigens to donor T cells in the inflammatory peritransplantation environment, thereby limiting GVHD. The sparing of LCs and DDC-IDCs by anti-CD52, as well as the recovery of donor-derived moDCs in a less inflammatory environment later after transplantation, may allow all these DCs to exert formative roles in graft-versus-tumor (GVT) reactions and immune reconstitution. Whether these results support a separation of deleterious from beneficial graft-host interactions at the level of antigen presentation, rather than solely at the level of T cells, will require further evaluation.
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PMID:Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation. 1239 88

Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath-1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45.7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4.1, P = 0.01] which were often recurrent in patients with severe acute or chronic graft-versus-host disease (GVHD) (OR 10.6, P = 0.03). Infection within the first 100 d (OR 5.0, P = 0.05) and PIV 3 (OR 9.2, P = 0.01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced-intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T-cell subset in this setting might also have been contributory factors.
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PMID:Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality. 1247 97

The anti-CD52 (Campath-1) monoclonal antibodies (Mabs) have a substantial history of use for controlling graft-versus-host disease in allogeneic bone marrow transplantation. Now, with the availability of a humanised form, alemtuzumab (Campath-1H), and the demonstration that this agent can reduce the tumour burden in B-CLL, a new niche may be found - as a potentially curative agent in which its tumour purging ability in vivo combines with its role as a conditioning agent in nonmyeloablative transplantation. Review of the literature shows that alemtuzumab has unique advantages as a method of depleting malignant lymphocytes, including those in patients resistant to conventional chemotherapy. Alemtuzumab can also be used in BMT for depletion of normal T and B lymphocytes of both the recipient and donor for prevention of graft rejection and GVHD. It allows good stem cell recovery with resultant rapid engraftment, has a low risk of EBV-triggered secondary malignancy and does not interfere with blood stem cell mobilisation. As a method of eliminating the malignant clone in B-CLL, alemtuzumab has shown remarkable efficacy in heavily pre-treated patients, a number of whom have progressed to autologous or allogeneic transplantation. Efficacy data are shown within the context of other transplantation data for B-CLL. These results indicate that the combination of tumour-depleting and immunosuppressive properties of alemtuzumab should be explored, with the hope of providing improved treatment options for elderly patients with advanced B-CLL or indolent lymphoma whose prognosis is too poor currently to allow treatment with traditional regimens of high-dose myeloablative chemotherapy.
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PMID:Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning? 1247 71

Haemorrhagic cystitis (HC) is an important cause of morbidity following stem cell transplantation (SCT) and has been associated with polyoma virus infection. We studied the incidence and outcome of polyoma virus infection in 58 T-cell-depleted SCT patients. T-cell depletion was carried out using Campath-1H, either 10 or 20 mg in vitro (n=33) or 50 or 100 mg in vivo (n=25) following conventional (n=35) or nonmyeloablative conditioning (n=23). A total of 21 patients (36%) had polyoma viruria at a median of 35 days (5-114); 30% among patients receiving Campath in vitro and 44% among those given in vivo. The only risk factor for polyoma viruria was graft-versus-host disease GVHD grade >or=2. The onset of polyoma viruria coincided with Cytomegalovirus (CMV) reactivation in all six patients who reactivated both viruses. Prolonged viruria (defined as polyoma viruria >2 weeks) was documented in 10 patients (17%) and this was associated with GVHD >or=grade 2. HC occurred in four patients. Prolonged viruria was associated with HC only in patients receiving unrelated donor grafts following conventional conditioning. HC was not observed following nonmyeloablative conditioning despite a higher incidence of prolonged viruria. Thus, HC was uncommon in patients with polyoma viruria following T-cell depletion with Campath, particularly after reduced intensity conditioning.
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PMID:Polyoma viruria following T-cell-depleted allogeneic transplants using Campath-1H: incidence and outcome in relation to graft manipulation, donor type and conditioning. 1263 29

Graft versus host disease (GVHD) remains the main barrier to successful allogeneic bone marrow transplant outcomes. Depletion of graft T cells is an effective way of reducing the incidence of acute and chronic GVHD, and a variety of methods have been used to achieve this depletion. Donor CD8+ T cells seem to be the critical effector cells; GVHD is reduced when the depletion process eliminates these cells, but not when CD4 cells are targeted alone. However, despite the successful reduction in GVHD, transplant outcomes are usually inferior with T-cell depleted transplants, because of increased graft failure, infections and relapse. Alternative approaches are needed. In vivo T-cell depletion, using antithymocyte globulin (ATG) as part of the conditioning regimen, seems an attractive option. Pre-transplant ATG lingers in the bone marrow to deplete engrafting donor T cells, but also depletes host T cells to prevent graft rejection and allow de-escalation of the conditioning regimen. It also avoids the need for graft manipulation with its associated costs, need for expertise and CD34+ cell loss. The efficacy of pre-transplant horse ATG remains anecdotal but it has been reported to modestly lower GVHD in single arm studies. Rabbit ATG has been studied in prospective randomised trials. There is evidence of a dose-response effect in reducing GVHD; however, there was no improvement in outcome, because of increased mortality associated with infection. In contrast, pre-transplant alemtuzumab (campath-1H) or an earlier version of this molecule (campath-1G), which target CD52+ cells, do appear to be effective in reducing both acute and chronic GVHD. There is speculation that this is not solely due to the effect of campath on T cells but that it may also be due to the elimination of host antigen-presenting cells (APC), which seem to be important in GVHD pathogenesis. Host APC are more efficient at expressing endogenous and exogenous host antigens on class I MHC to donor CD8+ cells than donor APC, which need to cross-prime exogenous antigen. Campath-1G eliminates host dendritic cells by the time of graft infusion, supporting this as a possible mechanism of action. Pre-transplant alemtuzumab has not yet been studied in a prospective randomised study, and this is required to quantify any benefit on outcome; despite this, published studies do show cause for optimism.
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PMID:T-cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation? 1274 51


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